AMPK Endothelial Cell Dysfunction and the Metabolic Syndrome (PROGRAM PROJECT)

AMPK 内皮细胞功能障碍和代谢综合征（计划项目）

• 批准号: 8231333
• 负责人: NEIL B RUDERMAN
• 金额: $ 149.94万
• 依托单位: BOSTON MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-15 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8231333
• 关键词: 5' -AMP-activated protein kinase; Affect; Age; Animals; Antiatherogenic; Aorta; Atherosclerosis; Biological; Blood Vessels; Capillarity; Cells; Central obesity; Cultured Cells; Diet; Disease; Dyslipidemias; Endothelial Cells; Endothelium; Enzymes; Exercise; Experimental Models; Fatty acid glycerol esters; Functional disorder; Glucose; Human; Hyperglycemia; Hypertension; Impairment; Insulin Resistance; Ischemia; Lipids; Liver; Metabolic syndrome; Mus; Muscle; Nature; Non-Insulin-Dependent Diabetes Mellitus; Oxidative Stress; Peripheral; Post-Translational Protein Processing; Predisposition; Prevention; Program Research Project Grants; Protein Kinase; Public Health; Research; Research Personnel; Risk Factors; STK11 gene; Signal Transduction; Sucrose; TNF gene; Testing; Tissues; Transgenic Mice; Vascular Endothelial Cell; angiogenesis; atherogenesis; base; feeding; in vivo; insight; lipid metabolism; new therapeutic target; novel; premature; premature atherosclerosis; prevent; programs; response

The metabolic syndrome has been defined clinically as a disorder characterized by dyslipidemia, hypertension, central obesity, hyperglycemia and a predisposition to premature atherosclerotic cardiovascular disease and type 2 diabetes. In addition it is associated with microvascular rarefaction and impaired angiogenesis. In both humans and experimental animals the metabolic syndrome is typically accompanied and preceded by insulin resistance, lipid abnormalities and a proinflammatory state. We and others have proposed that these abnormalities could be the result of dysregulation of the fuel-sensing enzyme AMP-activated protein kinase (AMPK). This program will focus on the endothelium, which is generally believed to be the first vascular cell altered during both atherogenesis and impaired angiogenesis. Two major hypotheses will be tested: 1) that the vascular abnormalities associated with the metabolic syndrome are caused in part by dysregulation of AMPK (decreased basal activity or impaired activation) in the endothelial cell as well as peripheral tissues and 2) that such dysregulation is the result of impairment of a SIRT1/LKB1 signaling mechanism that we have demonstrated regulates AMPK activity in various cultured cells and in the liver in vivo (See Project 1). The three projects will individually and collectively characterize the SIRT1/LKB1/AMPK mechanism in cultured vascular endothelial cells and determine the effects of its activation and inhibition on the proatherogenic effects of glucose, FFA and TNF? (Projects 1, 2) and the angiogenic response to ischemia (Project 3). We will also explore the hypothesis that oxidative stress causes post-translational modifications of SIRT1 that can be prevented by AMPK activation (Projects 2, 1). Finally, we will develop transgenic mice with an endothelial cell specific deletion of SIRT1 or LKB1 (Core B). We will then assess the effect of these deletions on muscle capillarity (Projects 3 and 1) and atherogenic changes in the aorta (Project 2) in control mice and mice fed a high-fat/high sucrose diet. In addition, we will assess the anti-atherogenic and pro-angiogenic effects of exercise in these mice (Projects 1-3). A program project grant is requested because of the interactive nature of the research and the use of experimental models that are most effectively studied by multiple investigators. The metabolic syndrome affects over 60,000,000 people in the U.S. over the age of 20 and is a major public health problem. The proposed studies should both yield novel insights into the biological bases for the premature atherosclerosis and impaired angiogenesis associated with this entity and suggest new therapeutic targets for their prevention.

代谢综合征在临床上被定义为以血脂异常、高血压、向心性肥胖、高血糖和易患过早动脉粥样硬化性心血管疾病和2型糖尿病为特征的疾病。此外，它还与微血管稀疏和血管生成受损有关。在人类和实验动物中，代谢综合征通常伴随并先于胰岛素抵抗、脂质异常和促炎症状态。我们和其他人提出，这些异常可能是燃料感应酶 AMP 激活蛋白激酶 (AMPK) 失调的结果。该计划将重点关注内皮细胞，通常认为内皮细胞是动脉粥样硬化形成和血管生成受损期间第一个发生改变的血管细胞。将测试两个主要假设：1) 与代谢综合征相关的血管异常部分是由内皮细胞和外周组织中的 AMPK 失调（基础活性降低或激活受损）引起的；2) 这种失调是 SIRT1/LKB1 信号机制受损的结果，我们已经证明 SIRT1/LKB1 信号机制在各种情况下调节 AMPK 活性。 培养细胞和体内肝脏（参见项目 1）。这三个项目将单独和共同表征培养血管内皮细胞中的 SIRT1/LKB1/AMPK 机制，并确定其激活和抑制对葡萄糖、FFA 和 TNF? 的促动脉粥样硬化作用的影响？ （项目 1、2）和对缺血的血管生成反应（项目 3）。我们还将探讨氧化应激导致 SIRT1 翻译后修饰的假设，而这种修饰可以通过 AMPK 激活来预防（项目 2、1）。最后，我们将开发内皮细胞特异性删除 SIRT1 或 LKB1 的转基因小鼠（核心 B）。然后，我们将评估这些缺失对对照小鼠和高脂肪/高蔗糖饮食小鼠的肌肉毛细血管（项目 3 和 1）和主动脉粥样硬化变化（项目 2）的影响。此外，我们将评估运动对这些小鼠的抗动脉粥样硬化和促血管生成作用（项目 1-3）。由于该研究的互动性质以及使用由多个研究人员最有效研究的实验模型，因此需要项目资助。代谢综合征影响着美国 20 岁以上超过 60,000,000 人，是一个重大的公共卫生问题。拟议的研究应该对与该实体相关的过早动脉粥样硬化和血管生成受损的生物学基础产生新的见解，并提出新的预防治疗靶点。